ArticleNature communications2023
Orthosteric and allosteric modulation of human HCAR2 signaling complex.
Article in Nature communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
11 citing papers in PubMed, 23 citations in OpenAlex.
- Article
- Hepatic SNHG9 links gut microbiota to liver protection in drug-induced liver injury.Nature communications · 2026Article
- Hydroxycarboxylic Acid Receptor 2 Mediates β-hydroxybutyrate's Antiseizure Effect in Mice.Annals of neurology · 2026Article
- Structural Perspectives on Biased Allostery of GPCR Signaling.Handbook of experimental pharmacology · 2026Review
- Utilizing Monocarboxylate Transporter 1-Mediated Blood-Brain Barrier Penetration for Glioblastoma Positron Emission Tomography Imaging with 6-[Molecular pharmaceutics · 2025Article
- Structures of G-protein coupled receptor HCAR1 in complex with Gi1 protein reveal the mechanistic basis for ligand recognition and agonist selectivity.PLoS biology · 2025Article
- Insights into the Activation Mechanism of HCA1, HCA2, and HCA3.Journal of medicinal chemistry · 2025Article
- Exposure to β-hydroxybutyrate reduces the operating set point and increases excitability in hippocampal circuitry of healthy mice.Frontiers in pharmacology · 2025Article
- β-Hydroxybutyrate enhances chondrocyte mitophagy and reduces cartilage degeneration in osteoarthritis via the HCAR2/AMPK/PINK1/Parkin pathway.Aging cell · 2024Article
- Multiple recent HCAR2 structures demonstrate a highly dynamic ligand binding and G protein activation mode.Nature communications · 2024Review
- Structure-guided engineering of biased-agonism in the human niacin receptor via single amino acid substitution.Nature communications · 2024Article
Corrections and comments
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Authors and funding
14 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hydroxycarboxylic acids are crucial metabolic intermediates involved in various physiological and pathological processes, some of which are recognized by specific hydroxycarboxylic acid receptors (HCARs). HCAR2 is one such receptor, activated by endogenous β-hydroxybutyrate (3-HB) and butyrate, and is the target for Niacin. Interest in HCAR2 has been driven by its potential as a therapeutic target in cardiovascular and neuroinflammatory diseases. However, the limited understanding of how ligands bind to this receptor has hindered the development of alternative drugs able to avoid the common flushing side-effects associated with Niacin therapy. Here, we present three high-resolution structures of HCAR2-Gi1 complexes bound to four different ligands, one potent synthetic agonist (MK-6892) bound alone, and the two structures bound to the allosteric agonist compound 9n in conjunction with either the endogenous ligand 3-HB or niacin. These structures coupled with our functional and computational analyses further our understanding of ligand recognition, allosteric modulation, and activation of HCAR2 and pave the way for the development of high-efficiency drugs with reduced side-effects.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.